Compositions and methods for treating hypertension

ABSTRACT

Disclosed herein are compositions and methods for delivering cannabidiol to subject in need of hypertension treatment. The disclosed compositions are orally delivered. Further disclosed are kits comprising the disclosed compositions as part of a method of delivering the cannabidiol-containing compositions.

FIELD

Disclosed herein are compositions and methods for delivering cannabidiolto subject in need of hypertension treatment. The disclosed compositionsare orally delivered.

Further disclosed are kits comprising the disclosed compositions as partof a method of delivering the cannabidiol-containing compositions.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a plot of the individual plasma concentration of CBD inAnimals 1-10 after oral administration of 25 mg/kg of the compositiondisclosed in Table 1.

FIG. 2 is the plot of the average plasma concentrations of CBD inAnimals 1-10 after oral administration of 25 mg/kg of the compositiondisclosed in Table 1.

FIG. 3 is a plot of the individual plasma concentration of CBD inAnimals 11-20 after oral administration of 25 mg/kg of the compositiondisclosed in Table 2.

FIG. 4 is the plot of the average plasma concentrations of CBD inAnimals 11-20 after oral administration of 25 mg/kg of the compositiondisclosed in Table 2.

FIG. 5 is a plot of the individual plasma concentration of CBD inAnimals 21-30 after oral administration of 25 mg/kg of the compositiondisclosed in Table 3.

FIG. 6 is the plot of the average plasma concentrations of CBD inAnimals 21-30 after oral administration of 25 mg/kg of the compositiondisclosed in Table 3.

FIG. 7 is a plot of the individual plasma concentration of CBD inAnimals 31-40 after oral administration of 25 mg/kg of the compositiondisclosed in Table 4.

FIG. 8 is the plot of the average plasma concentrations of CBD inAnimals 31-40 after oral administration of 25 mg/kg of the compositiondisclosed in Table 4.

FIG. 9 is a plot of the individual plasma concentration of CBD inAnimals 41-50 after oral administration of 25 mg/kg of the compositiondisclosed in Table 5.

FIG. 10 is the plot of the average plasma concentrations of CBD inAnimals 41-50 after oral administration of 25 mg/kg of the compositiondisclosed in Table 5.

FIG. 11 is the 24-hour plot of the systolic blood pressure of subjectsgiven the composition disclosed in Table 6 (●) versus placebo (○).

FIG. 12 is the 24-hour plot of the mean arterial pressure of subjectsgiven the composition disclosed in Table 6 (●) versus placebo (○).

FIG. 13 is the 24-hour plot of the diastolic blood pressure of subjectsgiven the composition disclosed in Table 6 (●) versus placebo (○).

DETAILED DESCRIPTION OF THE DISCLOSURE

The materials, compounds, compositions, articles, and methods describedherein may be understood more readily by reference to the followingdetailed description of specific aspects of the disclosed subject matterand the Examples included therein.

Also, throughout this specification, various publications arereferenced. The disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which the disclosed matterpertains. The references disclosed are also individually andspecifically incorporated by reference herein for the material containedin them that is discussed in the sentence in which the reference isrelied upon.

General Definitions

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

All percentages, ratios and proportions herein are by weight, unlessotherwise specified. All temperatures are in degrees Celsius (° C.)unless otherwise specified.

The terms “a” and “an” are defined as one or more unless this disclosureexplicitly requires otherwise.

Ranges may be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. The terms “comprise” (and any form of comprise, such as“comprises” and “comprising”), “have” (and any form of have, such as“has” and “having”), “include” (and any form of include, such as“includes” and “including”) and “contain” (and any form of contain, suchas “contains” and “containing”) are open-ended linking verbs. As aresult, an apparatus that “comprises,” “has,” “includes” or “contains”one or more elements possesses those one or more elements, but is notlimited to possessing only those elements. Likewise, a method that“comprises,” “has,” “includes” or “contains” one or more steps possessesthose one or more steps, but is not limited to possessing only those oneor more steps.

Any embodiment of any of the disclosed methods or compositions canconsist of or consist essentially of—rather thancomprise/include/contain/have—any of the described steps, elements,and/or features. Thus, in any of the claims, the term “consisting of” or“consisting essentially of” can be substituted for any of the open-endedlinking verbs recited above, in order to change the scope of a givenclaim from what it would otherwise be using the open-ended linking verb.The term “composition” is defined herein as a composition that does notrequire approval by a regulatory authority an can be offered for sale byany retail merchant, for example, pharmacies, grocery stores,convenience stores, department stores, and the like.

The feature or features of one embodiment may be applied to otherembodiments, even though not described or illustrated, unless expresslyprohibited by this disclosure or the nature of the embodiments.

Any embodiment of any of the disclosed compounds or methods can consistof or consist essentially of—rather thancomprise/include/contain/have—any of the described steps, elements,and/or features. Thus, in any of the claims, the term “consisting of” or“consisting essentially of” can be substituted for any of the open-endedlinking verbs recited above, in order to change the scope of a givenclaim from what it would otherwise be using the open-ended linking verb.

COMPOSITIONS

In one aspect disclosed compositions comprise:

-   -   A) a base composition; and    -   B) one or more delivery agents.        Base Compositions

According to the present disclosure the base compositions can compriseCBD oil. What is meant herein by the term “CBD oil” is thecannabidiol-containing extract from the hemp plant Cannabis sativa. TheCBD oil useful for preparing the disclosed compositions can be extractswhich are crude extracts containing less than about 80% by weight ofcannabidiol. As used herein CBD oil comprising less than about 80% byweight of cannabidiol is referred to a “crude CBD oil.” When using lowerpercentage extracts the formulator will necessarily adjust the amount ofCBD oil present in the disclosed compositions to ensure adequatedelivery of the desired amount of cannabidiol.

In one embodiment, the compositions comprise a “hemp distillate”comprising from about 80% to about 92% by weight of cannabidiol. In astill further embodiment isolated, pure cannabidiol can be used in thepresent compositions. When the hemp distillate comprising from 80% toabout 92% by weight cannabidiol is used, the term “CBD oil” applies. Insome descriptions of the “CBD oil” this ingredient can be referred to asa “CBD resin.”

Another aspect of the present disclosure relates the base compositions,comprise:

-   -   a) from about 0.5% to about 20% by weight of CBD oil;    -   b) from about 0.5% to about 60% by weight of one or more edible        oils; and    -   c) the balance a carrier.

In another embodiment of this aspect the base compositions, comprise:

-   -   a) from about 0.5% to about 20% by weight of CBD oil;    -   b) from about 0.5% to about 60% by weight of one or more edible        oils; and    -   c) the balance from about 20% to about 99% by weight of a        carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin,        guar, and psyllium.

In one embodiment of this aspect the compositions, comprise:

-   -   a) from about 2% to about 5% by weight of CBD oil;    -   b) from about 4% to about 15% by weight of sunflower oil; and    -   c) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin,        guar, and psyllium.

In a non-limiting example of this iteration the base compositions,comprise:

-   -   a) from about 2% to about 5% by weight of CBD oil;    -   b) from about 6% to about 15% by weight of sunflower oil;    -   c) from about 5% to about 20% of a bile salt; and    -   d) from about a carrier chosen from gum Arabic, inulin,        microcrystalline cellulose, D-lactose monohydrate, and quillaia.

In a further example the carrier is gum Arabic. In another example thecarrier is inulin. In a yet another example the carrier ismicrocrystalline cellulose. In a still further example the carrier isD-lactose monohydrate. In a still another example the carrier isquillaia.

In a further embodiment of this aspect the base compositions, comprise:

-   -   a) from about 0.5% to about 8% by weight of CBD oil;    -   b) from about 0.5% to about 15% by weight of coconut oil; and    -   c) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin,        guar, and psyllium.

In a further iteration of this embodiment the base compositions,comprise:

-   -   a) from about 2% to about 5% by weight of CBD oil;    -   b) from about 4% to about 15% by weight of coconut oil; and    -   c) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin,        guar, and psyllium.

In a non-limiting example of this iteration the base compositions,comprise:

-   -   a) from about 2% to about 5% by weight of CBD oil;    -   b) from about 0.5% to about 15% by weight of coconut oil;    -   c) from about 5% to about 15% of a bile salt; and    -   d) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, and quillaia.

In one embodiment of this aspect, the base composition comprises:

-   -   a) from about 0.5% to about 8% by weight of CBD oil;    -   b) from about 0.5% to about 15% by weight of coconut oil; and    -   c) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin,        guar, and psyllium.

In a further embodiment of this aspect the base compositions, comprise:

-   -   a) from about 0.5% to about 8% by weight of CBD oil;    -   b) from about 0.5% to about 15% by weight of coconut oil; and    -   c) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin,        guar, and psyllium.

In a further iteration of this embodiment the base compositions,comprise:

-   -   a) from about 2% to about 5% by weight of CBD oil;    -   b) from about 4% to about 15% by weight of coconut oil; and    -   c) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin,        guar, and psyllium.

In a non-limiting example of this iteration the base compositions,comprise:

-   -   a) from about 2% to about 5% by weight of CBD oil;    -   b) from about 0.5% to about 15% by weight of coconut oil;    -   c) from about 5% to about 15% of a bile salt; and    -   d) a carrier chosen from gum Arabic, inulin, microcrystalline        cellulose, D-lactose monohydrate, and quillaia.

The disclosed compositions comprise from about 0.5% to about 20% byweight of CBD oil. In one embodiment the disclosed base compositions cancomprise from about 0.5% to about 8% by weight of CBD oil. In oneembodiment, the base composition can comprise from about 1% to about 5%by weight of CBD oil. In another embodiment, the base composition cancomprise from about 2% to about 6% by weight of CBD oil. In a furtherembodiment, the base composition can comprise from about 2% to about 5%by weight of CBD oil. In a yet further embodiment, the base compositioncan comprise from about 3% to about 5% by weight of CBD oil. Forexample, the amount of CBD oil can be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%,2%, 3%, 4%, 5%, 6%, 7%, or 8% by weight or any fractional amounts, forexample, 1.5%, 3,25%, and 5.75%.

The addition of a carboxylic acid in some embodiments aid in theformulation a flowable powder for encapsulation or packaging asdescribed herein below, especially when the carboxylic acid serves toform a salt with one or more of the carriers or delivery agents.

The disclosed anti-hypertension compositions, comprise:

-   -   a) from about 5 mg to about 15 mg by weight of CBD oil; and    -   b) from about 5 mg to about 45 mg by weight of one or more        edible oils.

In one aspect the disclosed compositions, comprise:

-   -   a) from about 5 mg to about 15 mg by weight of CBD oil;    -   b) from about 5 mg to about 45 mg by weight of one or more        edible oils; and    -   c) the balance one or more carriers.

In one embodiment of this aspect the disclosed compositions, comprise:

-   -   a) from about 5 mg to about 15 mg by weight of CBD oil;    -   b) from about 5 mg to about 45 mg by weight of one or more        edible oils; and    -   c) from about 150 mg to about 500 mg by weight of one or more        carriers.

In one iteration of this embodiment the disclosed compositions,comprise:

-   -   a) from about 5 mg to about 12 mg by weight of CBD oil;    -   b) from about 5 mg to about 30 mg by weight of one or more        edible oils; and    -   c) from about 200 mg to about 350 mg by weight of one or more        carriers.

In another iteration of this embodiment the disclosed compositions,comprise:

-   -   a) from about 7 mg to about 12 mg by weight of CBD oil;    -   b) from about 7 mg to about 24 mg by weight of one or more        edible oils; and    -   c) from about 250 mg to about 350 mg by weight of one or more        carriers.

In one non-limiting example the disclosed compositions, comprise:

-   -   a) from about 5 mg to about 15 mg by weight of CBD oil;    -   b) from about 5 mg to about 45 mg by weight of one or more        edible oils; and    -   c) from about 200 mg to about 350 mg by weight of one or more        carriers chosen from gum Arabic, inulin, or mixtures thereof.

In one non-limiting example the disclosed compositions, comprise:

-   -   a) from about 5 mg to about 15 mg by weight of CBD oil;    -   b) from about 5 mg to about 45 mg by weight of one or more        edible oils;    -   c) from about 25 mg to about 45 mg by weight of one or more bile        salts; and    -   d) from about 200 mg to about 350 mg by weight of one or more        carriers chosen from gum Arabic, inulin, or mixtures thereof.

In a further non-limiting example the disclosed compositions, comprise:

-   -   a) about 10 mg by weight of CBD oil;    -   b) about 20 mg by weight of sunflower oil;    -   c) about 34 mg by weight of ox bile; and    -   c) about 278 mg by weight of gum Arabic.

In a further non-limiting example the disclosed compositions, comprise:

-   -   a) about 10 mg by weight of CBD oil;    -   b) about 20 mg by weight of coconut oil; and    -   c) about 240 mg by weight of inulin.

In a further aspect of the disclosed anti-hypertensive compositions, thecomposition comprise from about 5 mg to about 15 mg by weight of CBDoil. In one embodiment the base compositions can comprise from about 5mg to about 12 mg by weight of CBD oil. In another embodiment the basecompositions can comprise from about 7 mg to about 15 mg by weight ofCBD oil. In further embodiment the base compositions can comprise fromabout 7 mg to about 12 mg by weight of CBD oil. The base compositionscan comprise 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg,14 mg, or 15 mg by weight of CBD oil.

Edible Oils

The disclosed compositions comprise one or more edible oils. Thedisclosed edible oils include oils that are primarilytriglyceride-containing oils. Non-limiting examples of these oils arechosen from sunflower oil, coconut oil, canola oil, palm oil, soybeanoil, corn oil, safflower oil, and peanut oil.

In another non-limiting example the edible oil is sunflower oil. In afurther non-limiting example the edible oil is coconut oil. In a stillfurther non-limiting example the edible oil is canola oil. In a yetfurther non-limiting example the edible oil is palm oil. In a still yetnon-limiting example the edible oil is soybean oil. In anothernon-limiting example the edible oil is corn oil. In a still anothernon-limiting example the edible oil is safflower oil. In a yet anothernon-limiting example the edible oil is peanut oil.

The disclosed base compositions can comprise from about 0.5% to about60% by weight of edible oil. In one embodiment the base compositions cancomprise from about 3% to about 15% by weight of edible oil. In anotherembodiment the base compositions can comprise from about 5% to about 17%by weight of edible oil. In a further embodiment the base compositionscan comprise from about 7.5% to about 15% by weight of edible oil. In astill further embodiment the base compositions can comprise from about5% to about 10% by weight of edible oil. In a yet further embodiment thecompositions comprise from about 20% to about 40% by weight of one ormore edible oils. In a still yet further embodiment the compositions cancomprise from about 15% to about 30% by weight of one or more edibleoils.

The disclosed compositions can comprise from about 0.5% to about 60% byweight of one or more edible oils, for example, the amount of edible oilcan be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%,24%, 25% 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%,38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%,52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% by weight, or anyfractional amount thereof, of one or more edible oils.

According to this aspect the ratio of CBD oil to edible oil is fromabout 1:1 to about 1:4. For example, the ratio of CBD oil to edible oilcan be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8,1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8,1:2.9, or 1:3.

The disclosed base compositions of this aspect comprise from about 5 mgto about 45 mg by weight of an edible oil. In one embodiment the basecompositions can comprise from about 5 mg to about 30 mg by weight ofone or more edible oils. In another embodiment the base compositions cancomprise from about 5 mg to about 20 mg by weight of one or more edibleoils. In a further embodiment the base compositions can comprise fromabout 5 mg to about 15 mg by weight of one or more edible oils. In a yetfurther embodiment the base compositions can comprise from about 5 mg toabout 12 mg by weight of one or more edible oils. In a still furtherembodiment the base compositions can comprise from about 10 mg to about30 mg by weight of one or more edible oils. In a yet another embodimentthe base compositions can comprise from about 15 mg to about 25 mg byweight of one or more edible oils. The compositions can comprise 5 mg, 6mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, or 45 mg by weightof one or more edible oils.

The disclosed edible oils include oils that are primarilytriglyceride-containing oils. Ono-limiting examples of these oils arechosen from sunflower oil, coconut oil, canola oil, palm oil, soybeanoil, corn oil, safflower oil, and peanut oil.

In one non-limiting example, the pharmaceutical compositions compriseolive oil. In this example, high oleic acid olive oil can be used.

In another non-limiting example the edible oil is sunflower oil. In afurther non-limiting example the edible oil is coconut oil. In a stillfurther non-limiting example the edible oil is canola oil. In a yetfurther non-limiting example the edible oil is palm oil. In a still yetnon-limiting example the edible oil is soybean oil. In anothernon-limiting example the edible oil is corn oil. In a still anothernon-limiting example the edible oil is safflower oil. In a yet anothernon-limiting example the edible oil is peanut oil.

In another aspect highly unsaturated carboxylic acids derived fromplant-based triglycerides can be admixed with one or more edible oils.In this aspect, for example, a formulator having a base compositioncomprising 10% by weight of an edible oil, can substitute 5% of thatedible oil with 5% of a disclosed carboxylic acid.

Carriers

In one aspect the disclosed carriers are polysaccharides. Non-limitingexamples of poly saccharide carriers include inulin, galactogen,cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch,and partially hydrolyzed polysaccharides. In another aspect the carriersare sugar alcohols, for example, sorbitol, erythritol, xylitol,lactitol, maltitol, mannitol, hydrogenated starch hydrolysates,isomaltose, or any combination thereof. In a further aspect carriercomponent is based on a native or chemically modified agar, alginates,carrageenan gum, cellulose, chitosan, chitin, cyclodextrin, dextran,gellan gum, glycogen, glycosaminoglycan, gum karaya, inulin, pectin,polydextrose, xanthan gum, or any other starches, gums or otherpolysaccharide, including functionalized derivatives, dextrinized,hydrolyzed, oxidized, alkylated, hydroxyalkylated, acetylated,fractionated, and physically modified starches and mixtures thereof. Insome embodiments glycerin and/or propylene glycol can be added as acarrier.

In another aspect the carrier is chosen from gum Arabic, inulin,mannitol, silicon dioxide, colloidal silicon dioxide, microcrystallinecellulose, D-lactose monohydrate, tapioca starch, tapioca flour,quillaia, or mixtures thereof. In a further example the carrier is gumArabic. In another example the carrier is inulin. In a yet anotherexample the carrier is microcrystalline cellulose. In a still furtherexample the carrier is D-lactose monohydrate. In a still another examplethe carrier is quillaia. The carrier can be a combination of gum Arabic,inulin, microcrystalline cellulose, D-lactose monohydrate, or quillaia.

In one non-limiting example the carrier is mannitol, a non-limitingexample is Partek™ mannitol, available from Partek Inc. In a furthernon-limiting example the carrier is a microcrystalline cellulose. In astill further example the carrier is colloidal silicon dioxide.

The disclosed base compositions can comprise from about 50% to about 99%by weight of one or more carriers. In one embodiment disclosedcompositions can comprise from about 60% to about 95% by weight of oneor more carriers. In another embodiment the disclosed compositions cancomprise from about 60% to about 80% by weight of one or more carriers.In a yet another embodiment the disclosed compositions can comprise fromabout 75% to about 95% by weight of one or more carriers. In a furtherembodiment the disclosed compositions can comprise from about 65% toabout 90% by weight of one or more carriers. As such, the disclosed basecompositions can comprise 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% ofone or more carriers.

The disclosed base compositions can comprise from about 100 mg to about500 mg by weight of one or more carriers. In one embodiment the basecompositions comprise from about 250 mg to about 350 mg by weight of oneor more carriers. In another embodiment the base compositions comprisefrom about 150 mg to about 300 mg by weight of one or more carriers. Ina further embodiment the base compositions comprise from about 200 mg toabout 300 mg by weight of one or more carriers. In a yet furtherembodiment the base compositions comprise from about 300 mg to about 400mg by weight of one or more carriers. In one embodiment the basecompositions comprise from about 200 mg to about 450 mg by weight of oneor more carriers. The disclosed base compositions can comprise 100 mg,101 mg, 102, mg, 103, mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127mg, 128 mg, 129 mg, 130 mg 31 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172mg, 173 mg, 174 mg, 175 mg, 167 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 262mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271mg, 272 mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280mg, 281 mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289mg, 290 mg, 290 mg, 291 mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297mg, 298 mg, 299 mg, 300 mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306mg, 307 mg, 308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315mg, 316 mg, 317 mg, 318 mg, 319 mg, 320 mg, 321 mg, 322 mg, 323 mg, 324mg, 325 mg, 326 mg, 327 mg, 328 mg, 329 mg, 330 mg, 331 mg, 332 mg, 333mg, 334 mg, 335 mg, 336 mg, 337 mg, 338 mg, 339 mg, 340 mg, 341 mg, 342mg, 343 mg, 344 mg, 345 mg, 346 mg, 347 mg, 348 mg, 349 mg, 350 mg, 351mg, 352 mg, 353 mg, 354 mg, 355 mg, 356 mg, 357 mg, 358 mg, 359 mg, 360mg, 361 mg, 362 mg, 363 mg, 364 mg, 365 mg, 366 mg, 367 mg, 368 mg, 369mg, 370 mg, 371 mg, 372 mg, 373 mg, 374 mg, 375 mg, 376 mg, 377 mg, 378mg, 379 mg, 380 mg, 381 mg, 382 mg, 383 mg, 384 mg, 385 mg, 386 mg, 387mg, 388 mg, 389 mg, 390 mg, 390 mg, 391 mg, 392 mg, 393 mg, 394 mg, 395mg, 396 mg, 397 mg, 398 mg, 399 mg, 400 mg, 401 mg, 402 mg, 403 mg, 404mg, 405 mg, 406 mg, 407 mg, 408 mg, 409 mg, 410 mg, 411 mg, 412 mg, 413mg, 414 mg, 415 mg, 416 mg, 417 mg, 418 mg, 419 mg, 420 mg, 421 mg, 422mg, 423 mg, 424 mg, 425 mg, 426 mg, 427 mg, 428 mg, 429 mg, 430 mg, 431mg, 432 mg, 433 mg, 434 mg, 435 mg, 436 mg, 437 mg, 438 mg, 439 mg, 440mg, 441 mg, 442 mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449mg, 450 mg, 451 mg, 452 mg, 453 mg, 454 mg, 455 mg, 456 mg, 457 mg, 458mg, 459 mg, 460 mg, 461 mg, 462 mg, 463 mg, 464 mg, 465 mg, 466 mg, 467mg, 468 mg, 469 mg, 470 mg, 471 mg, 472 mg, 473 mg, 474 mg, 475 mg, 476mg, 477 mg, 478 mg, 479 mg, 480 mg, 481 mg, 482 mg, 483 mg, 484 mg, 485mg, 486 mg, 487 mg, 488 mg, 489 mg, 490 mg, 490 mg, 491 mg, 492 mg, 493mg, 494 mg, 495 mg, 496 mg, 497 mg, 498 mg, 499 mg, or 500 mg by weightof one or more carriers.

Bile Salts

The disclosed base compositions can further comprise from 5% to about20% by weight of a bile salt. Bile salts enhance the ability of thedisclosed compositions to target the duodenum. Non-limiting examples ofbile salts and/or bile acids includes steroid acids (and/or thecarboxylate anion thereof) and salts thereof, found in the bile of ananimal (e.g., a human), including cholic acid, cholate, deoxycholicacid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholicacid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholicacid, chenodeoxycholate, lithocholic acid, lithocolate, and the like.Taurocholic acid and/or taurocholate are referred to herein as TCA.

Bile salts are typically conjugated with glycine or taurine. Forexample, the term “bile acid” as used herein includes cholic acidconjugated with either glycine or taurine: glycocholate andtaurocholate, respectively (and salts thereof). Any reference to a bilesalt or bile acid used herein includes reference to an identicalcompound naturally or synthetically prepared. In one non-limitingexample the bile salt is ox bile.

The disclosed compositions can comprise from about 5% to about 20% byweight of one or more bile salts. In one embodiment the compositionscomprise from about 7.5% to about 20% by weight of one or more bilesalts. In one embodiment the compositions comprise from about 7.5% toabout 12.5% by weight of one or more bile salts. In one embodiment thecompositions comprise from about 15% to about 20% by weight of one ormore bile salts. In one embodiment the compositions comprise from about5% to about 15% by weight of one or more bile salts. In one embodimentthe compositions comprise from about 12% to about 15% by weight of oneor more bile salts. The compositions can comprise, for example, 5%, 6%,7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% byweight of one or more bile salts.

The disclosed compositions comprise from about 25 mg to about 50 mg byweight of one or more bile salts. In one embodiment, the compositionscomprise from about 30 mg to about 50 mg by weight of one or more bilesalts. In another embodiment, the compositions comprise from about 30 mgto about 40 mg by weight of one or more bile salts. In furtherembodiment, the compositions comprise from about 25 mg to about 40 mg byweight of one or more bile salts. In yet another embodiment, thecompositions comprise from about 25 mg to about 35 mg by weight of oneor more bile salts. The disclosed base compositions can comprise, forexample, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg 31 mg, 32 mg, 33 mg,34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, or 50 mg by weight one or morebile salts.

In a further aspect of the disclosed anti-hypertension compositioncomprises:

-   -   a) from about 10 mg to about 100 mg by weight of CBD oil;    -   b) from about 10 mg to about 300 mg by weight of sunflower oil;        and    -   c) the balance one or more carriers.

In one embodiment of this aspect the base composition comprises:

-   -   a) from about 10 mg to about 100 mg by weight of CBD oil;    -   b) from about 10 mg to about 300 mg by weight of sunflower oil;        and    -   c) from about 200 mg to about 800 mg by weight of one or more        carriers.

In one non-limiting example of this embodiment the base compositionscomprise:

-   -   a) from about 10 mg to about 100 mg by weight of CBD oil;    -   b) from about 10 mg to about 300 mg by weight of sunflower oil;    -   c) from about 50 mg to about 8 mg by weight of one ore more bile        salts; and    -   d) from about 200 mg to about 800 mg by weight of one or more        carriers.

In another non-limiting example of this embodiment the base compositionscomprise:

-   -   a) from about 10 mg to about 100 mg by weight of CBD oil;    -   b) from about 10 mg to about 300 mg by weight of sunflower oil;    -   c) from about 50 mg to about 80 mg by weight of one ore more        bile salts; and    -   d) from about 200 mg to about 800 mg by weight of one or more        carriers wherein the carriers are chosen from tapioca starch,        tapioca flour, silicon dioxide, and mixture thereof.

In another non-limiting example of this embodiment the base compositionscomprise:

-   -   a) from about 25 mg to about 40 mg by weight of CBD oil;    -   b) from about 50 mg to about 80 mg by weight of sunflower oil;    -   c) from about 60 mg to about 70 mg by weight of one ore more        bile salts; and    -   d) from about 500 mg to about 600 mg by weight of one or more        carriers wherein the carriers are chosen from tapioca starch,        tapioca flour, silicon dioxide, and mixture thereof

In Further non-limiting example of this embodiment the base compositionscomprise:

-   -   a) from about 75 mg to about 90 mg by weight of CBD oil;    -   b) from about 55 mg to about 70 mg by weight of sunflower oil;    -   c) from about 60 mg to about 70 mg by weight of one ore more        bile salts; and    -   d) from about 500 mg to about 600 mg by weight of one or more        carriers wherein the carriers are chosen from tapioca starch,        tapioca flour, silicon dioxide, and mixture thereof.

In a still further non-limiting example of this embodiment the basecompositions comprise:

-   -   a) about 81 mg by weight of CBD oil;    -   b) about 62 mg by weight of sunflower oil;    -   c) about 65 mg by weight of one ore more bile salts; and    -   d) about 575 mg by weight of one or more carriers wherein the        carriers are chosen from tapioca starch, tapioca flour, silicon        dioxide, and mixture thereof.

In another embodiment of this aspect the base composition comprises:

-   -   a) from about 20 mg to about 40 mg by weight of CBD oil;    -   b) from about 40 mg to about 80 mg by weight of sunflower oil;        and    -   c) from about 500 mg to about 600 mg by weight of one or more        carriers.

In one iteration of this embodiment the base composition comprises:

-   -   a) from about 70 mg to about 100 mg by weight of CBD oil;    -   b) from about 70 mg to about 200 mg by weight of sunflower oil;        and    -   c) from about 300 mg to about 450 mg by weight of one or more        carriers.

In one non-limiting example of this iteration the base compositioncomprises:

-   -   a) from about 70 mg to about 100 mg by weight of CBD oil;    -   b) from about 70 mg to about 200 mg by weight of sunflower oil;        and    -   c) from about 300 mg to about 450 mg by weight of one or more        carriers wherein the carriers are chosen from mannitol, silicon        dioxide, colloidal silicon dioxide, microcrystalline cellulose,        and mixture thereof.

In another non-limiting example of this iteration the base compositionscomprise:

-   -   a) from about 80 mg to about 95 mg by weight of CBD oil;    -   b) from about 160 mg to about 190 mg by weight of sunflower oil;        and    -   c) from about 300 mg to about 400 mg by weight of one or more        carriers wherein the carriers are chosen from mannitol, silicon        dioxide, colloidal silicon dioxide, microcrystalline cellulose,        and mixture thereof.

In a further iteration the base compositions comprise:

-   -   a) from about 80 mg to about 95 mg by weight of CBD oil;    -   b) from about 160 mg to about 190 mg by weight of sunflower oil;    -   c) from about 60 mg to about 70 mg by weight of one ore more        bile salts and    -   d) from about 300 mg to about 400 mg by weight of one or more        carriers wherein the carriers are chosen from mannitol, silicon        dioxide, colloidal silicon dioxide, microcrystalline cellulose,        and mixture thereof.

In a still further non-limiting example of this iteration the basecompositions comprise:

-   -   a) about 87 mg by weight of CBD oil;    -   b) about 174 mg by weight of sunflower oil;    -   c) about 65 mg by weight one or more bile salts; and    -   d) about 375 mg by weight of one or more carriers wherein the        carriers are chosen from mannitol, silicon dioxide, colloidal        silicon dioxide, microcrystalline cellulose.

In a still further embodiment of this aspect the base compositioncomprises:

-   -   a) from about 65 mg to about 85 mg by weight of CBD oil;    -   b) from about 135 mg to about 170 mg by weight of sunflower oil;        and    -   c) from about 300 mg to about 400 mg by weight of one or more        carriers.

In one iteration of this embodiment the base composition comprises:

-   -   a) from about 65 mg to about 85 mg by weight of CBD oil;    -   b) from about 135 mg to about 170 mg by weight of sunflower oil;        and    -   c) from about 300 mg to about 400 mg by weight of one or more        carriers wherein the carriers are chosen from mannitol, silicon        dioxide, colloidal silicon dioxide, microcrystalline cellulose,        and mixture thereof.

In one non-limiting example of this iteration the base compositioncomprises:

-   -   a) from about 70 mg to about 80 mg by weight of CBD oil;    -   b) from about 145 mg to about 160 mg by weight of sunflower oil;        and    -   c) from about 300 mg to about 350 mg by weight of one or more        carriers wherein the carriers are chosen from mannitol, silicon        dioxide, colloidal silicon dioxide, microcrystalline cellulose,        and mixture thereof.

In another non-limiting example of this iteration the base compositioncomprises:

-   -   a) from about 70 mg to about 80 mg by weight of CBD oil;    -   b) from about 145 mg to about 160 mg by weight of sunflower oil;    -   c) from about 5 mg to about 8 mg by weight of one or more bile        salts; and    -   d) from about 300 mg to about 350 mg by weight of one or more        carriers wherein the carriers are chosen mannitol, silicon        dioxide, colloidal silicon dioxide, microcrystalline cellulose,        and mixture thereof.

In a further non-limiting example of this iteration the base compositioncomprises:

-   -   a) about 76 mg by weight of CBD oil;    -   b) about 152 mg by weight of sunflower oil;    -   c) about 7 mg by weight of one or more bile salts; and    -   d) about 335 mg by weight of one or more carriers wherein the        carriers are chosen from mannitol, silicon dioxide, colloidal        silicon dioxide, microcrystalline cellulose, and mixture        thereof.

In another example, a base composition comprises:

-   -   a) from about 5 mg to about 15 mg by weight of CBD oil;    -   b) from about 5 mg to about 60 mg by weight of an admixture of a        carboxylic acids derived from a plant-based triglyceride and one        or more edible oils, wherein the ratio of the carboxylic acid        and the edible oils is from about 1:9 to about 9:1; and    -   c) from about 100 mg to about 300 mg by weight of one or more        carriers.

METHODS

Disclosed herein are methods for treating hypertension in a subject inneed of treatment, comprising administering to the subject in need aneffective amount of a composition defined herein above.

In one aspect of the disclosed method a total dosage of the disclosedcomposition is from about 90 mg to about 450 mg over the course of 24hours depending upon the severity of the hypertension. For an averagehum weighing 60 kg, this equates to from about 1.5 mg/kg to about 75mg/kg per 24 hours.

In one embodiment the dosage per day is from about 90 mg to about 150mg. In a further embodiment the dosage per day is from about 140 mg toabout 250 mg. In another embodiment the dosage per day is from about 200mg to about 400 mg. In a still further embodiment the dosage per day isfrom about 300 mg to about 450 mg. In a yet further embodiment thedosage per day is from about 250 mg to about 350 mg.

The dosage of one or more disclosed compositions can be from about 90 mgto about 450 mg per 24 hours, for example, 90 mg, 91 mg, 92 mg, 93 mg,94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102, mg, 103,mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130mg 31 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175mg, 167 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 262 mg, 263 mg, 264 mg, 265mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281 mg, 282 mg, 283mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 290 mg, 291mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, 300mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg, 308 mg, 309mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318mg, 319 mg, 320 mg, 321 mg, 322 mg, 323 mg, 324 mg, 325 mg, 326 mg, 327mg, 328 mg, 329 mg, 330 mg, 331 mg, 332 mg, 333 mg, 334 mg, 335 mg, 336mg, 337 mg, 338 mg, 339 mg, 340 mg, 341 mg, 342 mg, 343 mg, 344 mg, 345mg, 346 mg, 347 mg, 348 mg, 349 mg, 350 mg, 351 mg, 352 mg, 353 mg, 354mg, 355 mg, 356 mg, 357 mg, 358 mg, 359 mg, 360 mg, 361 mg, 362 mg, 363mg, 364 mg, 365 mg, 366 mg, 367 mg, 368 mg, 369 mg, 370 mg, 371 mg, 372mg, 373 mg, 374 mg, 375 mg, 376 mg, 377 mg, 378 mg, 379 mg, 380 mg, 381mg, 382 mg, 383 mg, 384 mg, 385 mg, 386 mg, 387 mg, 388 mg, 389 mg, 390mg, 390 mg, 391 mg, 392 mg, 393 mg, 394 mg, 395 mg, 396 mg, 397 mg, 398mg, 399 mg, 400 mg, 401 mg, 402 mg, 403 mg, 404 mg, 405 mg, 406 mg, 407mg, 408 mg, 409 mg, 410 mg, 411 mg, 412 mg, 413 mg, 414 mg, 415 mg, 416mg, 417 mg, 418 mg, 419 mg, 420 mg, 421 mg, 422 mg, 423 mg, 424 mg, 425mg, 426 mg, 427 mg, 428 mg, 429 mg, 430 mg, 431 mg, 432 mg, 433 mg, 434mg, 435 mg, 436 mg, 437 mg, 438 mg, 439 mg, 440 mg, 441 mg, 442 mg, 443mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, or 450 mg per 24hours.

Preparation Example 1

The following additions were made using a stainless-steel reactionvessel, paddle, and scrapper to assist in the formation of theadmixtures. High oleic acid olive oil (90 g) was charged to a reactionvessel and stirred while heating to about 75° C. Cannabidiol (44.97 g,of a 99.378% sample) was combined with the high oleic acid olive oil andthe admixture was stirred at about 75° C. until homogeneous. To areaction vessel containing Aeroperl® 300 (80.62 g) was slowly added thecannabidiol/high oleic acid olive oil admixture with continuous andefficient stirring until homogeneous. Parteck-M® 100 mannitol (80.62 g)was added to the reaction mixture smith continuous stirring at 75° C.The contents of the vessel was spread evenly on a dehydrator tray andthe tray was then placed in a convection air flow dehydrator at about65° C. for 90 minutes. The trays were then allowed to cool to roomtemperature. The dehydrated admixture was transferred to stainless-steelvessel and deoxycholic acid (3.86 g) was added with continuous stirringuntil the admixture was homogeneous. The yield was of the total productwas approximately 309 g. The composition for testing was formed intocapsules having the quantities disclosed in Table 1.

The following additions were made using a stainless-steel reactionvessel, paddle, and scrapper to assist in the formation of theadmixtures. Sunflower oil (25.52 g) was charged to a reaction vessel andstirred while heating to about 75° C. CBD oil (12.76 g, of a 78.33%sample) was melted at about 75° C. then combined with the sunflower oiland stirred for 2 hours then at stirred at 80° C. for 30 minutes withefficient stirring to produce a homogeneous admixture. To a secondstainless-steel is charged gum Arabic (231.73 g). To the gum Arabic isadded the CBD oil/sunflower oil admixture with efficient stirring. (Notethe resulting admixture is clumpy and must be worked into a homogeneousstate. The contents of the vessel was spread evenly on a dehydrator trayand the tray was then placed in a convection air flow dehydrator atabout 65° C. for 90 minutes. After cooling, the admixture is sifted tobreak up any clumps. To a clean stainless-steel vessel is charged oxbile salt (30 g). To the ox bile salt the sifted admixture is added andthe admixture is efficiently mixed for 20 minutes. The final admixtureyields 284 g. The composition for testing was formed into capsuleshaving the quantities disclosed in Table 5.

Animal Studies

TABLE 1 Ingredients % mg CBD oil¹ 3.2 10 Sunflower oil 6.4 20 Gum Arabic90.4 278 Total 100 308 1. Contains 78.33% cannabidiol

TABLE 2 Ingredients % mg CBD oil¹ 2.9 10 Sunflower oil 5.8 20 Ox bile 1034.2 Gum Arabic 81.3 278 Total 100 342.2 1. Contains 78.33% cannabidiol

TABLE 3 Ingredients % mg CBD oil² 3.7 10 Coconut oil 7.4 20 Inulin 88.9239.14 Total 100 269.14 2. Contains 89.73% cannabidiolNanoemulsions

CBD oil (10 g) and sunflower oil (10 g) is combined with 100 g ofD-lactose monohydrate to form a homogeneous admixture. The admixture isthen metered into 212.5 gm of quillaja in 467.5 mL of water to form apre-emulsion. The pre-emulsion is then passed through a high pressuremicrofluidizer homogenizer to afford the liquid nanoemulsion.

TABLE 4 Ingredients % mg Cannabidiol³ 6.5 10 Sunflower oil 6.6 10D-lactose monohydrate 6.6 10 quillaia 25.8 37.5 water 54.4 83.5 Total100 151 3. Contains 99.65% cannabidiol

TABLE 5 Ingredients % mg CBD oil³ 6.5 10 Sunflower oil 6.6 10 D-lactosemonohydrate 6.6 10 quillaia 25.8 37.5 water 54.4 83.5 Total 100 151 2.Contains 89.73% cannabidiol

Individual and Average Plasma Concentrations (ng/mL) and PharmacokineticParameters for CBD After Oral Administration of the Composition of Table1 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 1)

TABLE 1 Sample Animal number time (hr) 1 2 3 4 5 0.033 BLOQ BLOQ BLOQBLOQ BLOQ 0.067 1.71 BLOQ 0.549 2.70 1.22 0.1 3.01 2.84 1.84 6.40 4.070.13 539 3.69 3.85 12.0 7.52 2.0 21.7 8.39 10.2 20.2 17.7 0.25 37.4 13.022.3 31.5 37.0 0.5 116 62.6 39.6 59.4 62.8 0.75 191 95.0 73.7 55.2 79.41.0 174 84.2 75.9 53.4 80.4 Dose (mg/kg) 0.296 0.288 0.288 0.286 0.286Vol. dosed 1.48 1.44 1.44 1.42 1.43 (mL) C_(max) (ng/mL) 191 95.0 75.959.4 80.4 t_(max) (hr) 0.75 0.75 1.0 0.5 1.0 t_(1/2) ND² ND² ND³ ND² ND³MRT_(last) (hr) 0.697 0.699 0.696 0.616 0.653 AUC_(last) 106 52.7 42.042.2 52.8 (hr · ng/mL) AUC_(∞) ND³ ND² ND³ ND² ND³ (hr · ng/mL)AUC_(last)/D 4.23 2.11 1.68 1.69 2.11 (hr · kg · ng/ mL/mg) AUC_(∞)/DND² ND² ND³ ND² ND³ (hr · kg · ng/ mL/mg) 1. Dose-normalized by dividingthe parameter by the nominal dose in mg/kg. 2. Not determined due to alack of quantifiable data points trailing the Cmax. 3. Not determinedbecause the terminal elimination phase was not observed. BLOQ = belowthe limit of quantitation (1 ng/mL)

TABLE II Sample Animal number time (hr) 6 7 8 9 10 0.033 BLOQ BLOQ BLOQ0.570 2.31 0.067 0.692 BLOQ 1.66 3.12 9.67 0.1 1.70 1.10 5.28 5.32 14.00.13 4.78 1.92 6.82 9.80 23.3 2.0 11.0 5.67 17.1 16.8 25.5 0.25 26.210.1 21.9 29.2 38.4 0.5 83.6 53.1 114 92.1 102 0.75 114 77.6 128 80.0174 1.0 133 78.9 89.2 57.9 188 Dose (mg/kg) 0.300 0.289 0.286 0281 0.287Vol. dosed 1.50 1.45 1.43 1.41 1.44 (mL) C_(max) (ng/mL) 133 78.9 12892.1 188 t_(max) (hr) 1.0 1.0 0.75 0.50 1.0 t_(1/2) ND³ ND³ ND² ND² ND³MRT_(last) (hr) 0.699 0.708 0.660 0.623 0.696 AUC_(last) 70.9 44.5 76.556.4 102 (hr · ng/mL) AUC_(∞) ND³ ND³ ND² ND² ND³ (hr · ng/mL)AUC_(last)/D 2.84 1.78 3.06 2.26 4.07 (hr · kg · ng/ mL/mg) AUC_(∞)/DND³ ND³ ND² ND² ND³ (hr · kg · ng/ mL/mg) 1. Dose-normalized by dividingthe parameter by the nominal dose in mg/kg. 2. Not determined due to alack of quantifiable data points trailing the Cmax. 3. Not determinedbecause the terminal elimination phase was not observed. BLOQ = belowthe limit of quantitation (1 ng/mL)

TABLE III Provides the mean and standard deviation for the results ofAnimals 1-10.

TABLE III Sample time (hr) mean SD 0.033 1.44 ND 0.067 2.67 2.97 0.104.56 3.75 0.13 7.91 6.19 0.20 15.4 6.37 0.25 26.7 9.96 0.50 78.5 26.80.75 107 45.1 1.0 101 47.1 Dose (mg/kg) 0.289 0.005 Vol. dosed (mL) 1.450.03 C_(max) (ng/mL) 112 46.6 t_(max) (hr) 0.83 0.21 t_(1/2) ND NDMRT_(last) (hr) 0.675 0.0341 AUC_(last) (hr · ng/mL) 64.6 23.6 AUC_(∞)(hr · ng/mL) ND ND AUC_(last)/D 2.58 0.946 (hr · kg · ng/mL/mg)AUC_(∞)/D ND ND (hr · kg · ng/mL/mg)

Individual and Average Plasma Concentrations (ng/mL) and PharmacokineticParameters for CBD After Oral Administration of the Composition of Table2 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 2)

TABLE IV Sample Animal number time (hr) 11 12 13 14 15 0.033 BLOQ BLOQBLOQ BLOQ BLOQ 0.067 2.91 1.29 1.77 2.76 BLOQ 0.10 6.24 5.39 7.75 8.673.23 0.13 15.2 9.32 17.7 18.4 5.57 0.20 22.0 19.7 29.3 22.3 15.9 0.2545.0 40.6 84.1 40.9 24.4 0.50 188 144 310 168 84.5 0.75 243 307 389 200125 1.0 223 325 372 171 112 Dose (mg/kg) 0.297 0.287 0.282 0.287 0.293Vol. dosed 149 1.44 141 1.44 1.47 (mL) C_(max) (ng/mL) 243 325 389 200125 t_(max) (hr) 0.75 1.0 2.75 0.75 0.75 t_(1/2) ND² ND³ ND² ND² ND²MRT_(last) (hr) 0.684 0.732 0.683 0.670 0.689 AUC_(last) 145 161 237 12271.4 (hr · ng/mL) AUC_(∞) ND² ND³ ND² ND² ND² (hr · ng/mL) AUC_(last)/D5.79 6.45 9.47 4.89 2.85 (hr · kg · ng/ mL/mg) AUC_(∞)/D ND² ND³ ND² ND²ND² (hr · kg · ng/ mL/mg) 1. Dose-normalized by dividing the parameterby the nominal dose in mg/kg 2. Not determined due to a lack ofquantifiable data points trailing the Cmax 3. Not determined because theterminal elimination phase was not observed. BLOQ = below the limit ofquantitation (1 ng/mL)

TABLE V Sample Animal number time (hr) 16 17 18 18 20 0.033 BLOQ BLOQBLOQ BLOQ BLOQ 0.067 5.89 5.94 2.05 2.64 4.42 0.10 17.0 15.1 6.86 6.536.01 0.13 23.6 24.8 10.4 12.6 14.0 0.20 38.7 47.1 20.7 27.3 23.1 0.2571.4 79.4 49.2 45.7 45.2 0.50 156 339 105 93.2 99.8 0.75 120 434 155 128191 1.0 92.0 316 133 123 106 Dose (mg/kg) 0.293 0.284 0.297 0.293 0.287Vol. dosed 1.47 1.42 1.49 1.47 1.44 (mL) C_(max) (ng/mL) 156 434 155 128191 t_(max) (hr) 0.50 0.75 0.75 0.75 0.75 t_(1/2) ND² ND² ND² ND³ ND²MRT_(last) (hr) 0.596 0.670 0.670 0.664 0.669 AUC_(last) 95.4 249 91.180.1 95.2 (hr · ng/mL) AUC_(∞) ND² ND² ND² ND³ ND² (hr · ng/mL)AUC_(last)/D 3.82 9.98 3.64 3.20 3.81 (hr · kg · ng/ mL/mg) AUC_(∞)/DND² ND² ND² ND³ ND² (hr · kg · ng/ mL/mg) 1. Dose-normalized by dividingthe parameter by the nominal dose in mg/kg. 2. Not determined due to alack of quantifiable data points trailing the Cmax. 3. Not determinedbecause the terminal elimination phase was not observed. BLOQ = belowthe limit of quantitation (1 ng/mL)

TABLE VI provides the mean and standard deviation for the results ofAnimals 11-20.

TABLE VI Sample time (hr) mean SD 0.033 ND ND 0.067 3.30 1.72 0.10 8.284.36 0.13 15. 6.13 0.20 26.6 9.56 0.25 52.6 19.2 0.50 169 89.3 0.75 229113 1.0 197 105 Dose (mg/kg) 0.290 0.005 Vol. dosed (mL) 1.45 0.03C_(max) (ng/mL) 235 111 t_(max) (hr) 0.75 0.12 t_(1/2) ND ND MRT_(last)(hr) 0.673 0.0333 AUC_(last) (hr · ng/mL) 135 63.7 AUC_(∞) (hr · ng/mL)ND ND AUC_(last)/D 5.39 2.55 (hr · kg · ng/mL/mg) AUC_(∞)/D ND ND (hr ·kg · ng/mL/mg)

Individual and Average Plasma Concentrations (ng/mL) and PharmacokineticParameters for CBD After Oral Administration of the Composition of Table3 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 3)

TABLE VII Sample Animal number time (hr) 21 22 23 24 25 0.033 BOLQ BOLQBOLQ BOLQ BOLQ 0.067 BOLQ BOLQ NS BOLQ BOLQ 0.1 0.72 BOLQ BOLQ BOLQ BOLQ0.13 1.15 BOLQ 0.597 BOLQ BOLQ 2.0 2.55 0.516 1.61 0.918 1.66 0.25 3.250.884 2.60 1.71 3.56 0.5 5.44 2.15 9.37 13.8 20.5 0.75 12.2 6.08 11.824.3 28.9 1.0 16.1 7.19 15.2 31.3 32.6 Dose (mg/kg) 0.304 0.303 0.3250.314 0.336 Vol. dosed 1.52 1.52 1.63 1.57 1.68 (mL) C_(max) (ng/mL)16.1 7.19 15.2 31.3 32.6 t_(max) (hr) 1.0 1.0 1.0 1.0 1.0 t_(1/2) ND²ND² ND² ND² ND² MRT_(last) (hr) 0.719 0.752 0.701 0.747 0.716 AUC_(last)7.16 3.12 7.71 13.7 17.1 (hr · ng/mL) AUC_(∞) ND² ND² ND² ND² ND² (hr ·ng/mL) AUC_(last)/D 0.286 0.125 0.308 0.550 0.682 (hr · kg · ng/ mL/mg)AUC_(∞)/D ND² ND² ND² ND² ND² (hr · kg · ng/ mL/mg) 1. Dose-normalizedby dividing the parameter by the nominal dose in mg/kg. 2. Notdetermined due to a lack of quantifiable data points trailing the Cmax.3. Not determined because the terminal elimination phase was notobserved. BLOQ = below the limit of quantitation (1 ng/mL)

TABLE VIII Sample Animal number time (hr) 26 27 28 29 30 0.033 BOLQ BOLQBOLQ BOLQ BOLQ 0.067 BOLQ BOLQ 2.97 BOLQ BOLQ 0.1 BOLQ BOLQ 6.67 0.743BOLQ 0.13 0.722 BOLQ 7.08 1.85 1.48 2.0 1.91 1.26 11.2 4.24 4346 0.252.99 2.48 14.4 6.97 7.60 0.5 7.86 13.3 18.0 16.4 33.7 0.75 16.5 28.942.9 16.5 38.4 1.0 15.3 35.8 26.6 21.8 39.1 Dose 0.292 0.296 0.309 0.2860287 (mg/kg) Vol. dosed 1.46 1.48 1.55 1.43 1.44 (mL) C_(max) 16.5 35.842.9 21.8 39.1 (ng/mL) t_(max) (hr) 0.75 1.0 0.75 1.0 1.0 t_(1/2) ND²ND² ND³ ND² ND² MRT_(last) (hr) 0.712 0754 0.652 0.663 0.682 AUC_(last)8.60 15.5 22.0 12.4 24.4 (hr · ng/mL) AUC_(∞) ND² ND² ND³ ND² ND² (hr ·ng/mL) AUC_(last)/D 0.344 0.619 0.495 0.495 0.976 (hr · kg · ng/ mL/mg)AUC_(∞)/D ND² ND² ND³ ND² ND² (hr · kg · ng/ mL/mg) 1.Dose-normalized bydividing the parameter by the nominal dose in mg/kg. 2.Not determineddue to a lack of quantifiable data points trailing the Cmax. 3.Notdetermined because the terminal elimination phase was not observed. BLOQ= below the limit of quantitation (1 ng/mL)

TABLE XIX provides the mean and standard deviation for the results ofAnimals 21-30.

TABLE XIX Sample time (hr) mean SD 0.033 ND ND 0.067 ND ND 0.10 2.723.42 0.13 2.20 2.44 0.20 3.03 3.15 0.25 4.64 4.04 0.50 14.1 8.98 0.7522.6 12.1 1.0 24.1 10.6 Dose (mg/kg) 0.305 0.016 Vol. dosed (mL) 1.530.08 C_(max) (ng/mL) 25.8 12.0 t_(max) (hr) 0.95 0.11 t_(1/2) ND NDMRT_(last) (hr) 0.710 0.0260 AUC_(last) (hr · ng/mL) 13.2 6.78 AUC_(∞)(hr · ng/mL) ND ND AUC_(last)/D 0.527 0.271 (hr · kg · ng/mL/mg)AUC_(∞)/D ND ND (hr · kg · ng/mL/mg)

Individual and Average Plasma Concentrations (ng/mL) and PharmacokineticParameters for CBD After Oral Administration of the Composition of Table4 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 4)

TABLE X Sample Animal number time (hr) 31 32 33 34 35 0.033 BOLQ BOLQBOLQ BOLQ 1.19 0.067 4.23 2.41 3.98 2.98 8.71 0.10 8.33 4.62 3.67 6.3618.2 0.13 15.0 5.90 8.09 13.7 27.2 0.20 23.1 9.06 11.9 26.7 32.2 0.2538.0 12.6 20.7 36.4 32.2 0.50 16.1 31.0 34.0 63.0 90.5 0.75 15.1 46.556.9 113 151 1.0 47.6 50.8 46.5 154 155 Dose (mg/kg) 0.281 0.291 0.2840.292 0.283 Vol. dosed 1.41 1.46 1.42 1.46 1.42 (mL) C_(max) (ng/mL)47.6 50.8 56.9 154 155 t_(max) (hr) 1.0 1.0 0.75 1.0 1.0 t_(1/2) ND² ND²ND³ ND² ND² MRT_(last) (hr) 0.595 0.683 0.658 0.703 0.685 AUC_(last)37.0 28.7 33.0 71.3 88.8 (hr · ng/mL) AUC_(∞) ND² ND² ND³ ND² ND² (hr ·ng/mL) AUC_(last)/D 1.48 1.15 1.32 2.85 3.55 (hr · kg · ng/ mL/mg)AUC_(∞)/D ND² ND² ND³ ND² ND² (hr · kg · ng/ mL/mg) 1. Dose-normalizedby dividing the parameter by the nominal dose in mg/kg. 2. Notdetermined due to a lack of quantifiable data points trailing the Cmax.3. Not determined because the terminal elimination phase was notobserved. BLOQ = below the limit of quantitation (1 ng/mL)

TABLE XI Sample Animal number time (hr) 36 37 38 39 40 0.033 6.27 BOLQ6.01 0.614 BOLQ 0.067 5.56 9.90 25.6 1.91 2.63 0.10 11.8 6.17 27.4 3.494.53 0.13 18.7 18.7 43.6 7.30 7.64 0.20 31.8 18.4 50.1 7.13 9.07 0.2536.9 22.3 46.5 16.8 9.46 0.50 44.8 31.6 84.3 34.8 30.7 0.75 59.7 40.291.5 34.1 59.3 1.0 44.7 33.8 82.8 46.7 76.8 Dose (mg/kg) 0.279 0.2670.287 0.284 0.279 Vol. dosed 1.40 1.34 1.44 1.42 1.40 (mL) C_(max)(ng/mL) 59.7 40.2 91.5 46.7 76.8 t_(max) (hr) 0.75 0.75 0.75 1.0 1.0t_(1/2) ND³ ND³ ND³ ND² ND² MRT_(last) (hr) 0.598 0.603 0.597 0.6530.724 AUC_(last) 10.7 28.1 68.4 26.6 34.7 (hr · ng/mL) AUC_(∞) ND³ ND³ND³ ND² ND² (hr · ng/mL) AUC_(last)/D 1.63 1.12 2.74 1.06 1.39 (hr · kg· ng/ mL/mg) AUC_(∞)/D ND³ ND³ ND³ ND² ND² (hr · kg · ng/ mL/mg) 1.Dose-normalized by dividing the parameter by the nominal dose in mg/kg.2. Not determined due to a lack of quantifiable data points trailing theCmax. 3. Not determined because the terminal elimination phase was notobserved. BLOQ = below the limit of quantitation (1 ng/mL)

TABLE XII provides the mean and standard deviation for the results ofAnimals 31-40.

TABLE XII Sample time (hr) mean SD 0.033 2.11 2.61 0.067 6.79 7.13 0.109.46 7.76 0.13 16.6 11.6 0.20 21.9 13.7 0.25 27.2 12.5 0.50 49.1 22.60.75 69.7 37.4 1.0 73.9 45.0 Dose (mg/kg) 0.283 0.007 Vol. dosed (mL)1.42 0.03 C_(max) (ng/mL) 77.9 43.1 t_(max) (hr) 0.90 0.13 t_(1/2) ND NDMRT_(last) (hr) 0.650 0.0488 AUC_(last) (hr · ng/mL) 45.7 22.0 AUC_(∞)(hr · ng/mL) ND ND AUC_(last)/D 1.83 0.882 (hr · kg · ng/mL/mg)AUC_(∞)/D ND ND (hr · kg · ng/mL/mg)

Individual and Average Plasma Concentrations (ng/mL) and PharmacokineticParameters for CBD After Oral Administration of the Composition of Table5 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 5)

TABLE XIII Sample Animal number time (hr) 41 42 43 44 45 0.033 BOLQ0.521 1.59 BOLQ BOLQ 0.067 4.50 5.30 8.02 3.11 5.35 0.10 16.5 14.1 17.53.14 9.37 0.13 20.7 19.3 26.4 5.72 20.1 0.20 521.0 39.5 56.5 9.71 37.50.25 31.7 55.0 61.0 14.5 45.6 0.50 72.9 92.3 81.4 63.8 101 0.75 84.1 11693.2 42.2 102 1.0 77.8 114 93.1 68.3 127 Dose (mg/kg) 0.297 0.289 0.2850.283 0.270 Vol. dosed 1.49 1.45 1.45 1.42 1.35 (mL) C_(max) (ng/mL)84.1 116 93.2 68.3 127 t_(max) (hr) 0.75 0.75 0.75 1.0 1.0 t_(1/2) ND²ND³ ND³ ND³ ND³ MRT_(last) (hr) 0.639 0.640 0.607 0.657 0.647 AUC_(last)56.7 78.5 70.0 38.3 77.2 (hr · ng/mL) AUC_(∞) ND² ND³ ND³ ND³ ND³ (hr ·ng/mL) AUC_(last)/D 2.27 3.14 2.80 1.53 3.09 (hr · kg · ng/ mL/mg)AUC_(∞)/D ND² ND³ ND³ ND³ ND³ (hr · kg · ng/ mL/mg) 1. Dose-normalizedby dividing the parameter by the nominal dose in mg/kg. 2. Notdetermined due to a lack of quantifiable data points trailing the Cmax.3. Not determined because the terminal elimination phase was notobserved. BLOQ = below the limit of quantitation (1 ng/mL)

TABLE XIV Sample Animal number time (hr) 46 47 48 49 50 0.033 2.34 BLOQBLOQ 0.950 3.04 0.067 8.58 3.37 1.26 4.25 17.1 0.1 14.2 5.85 3.18/ 6.4137.6 0.13 19.6 9.35 6.38 13.1 41.7 2.0 27.6 13.8 11.1 13.6 47.9 0.2558.9 16.4 19.3 28.1 55.2 0.5 124 49.5 31.7 52.5 105 0.75 188 73.5 48.0117 143 1.0 188 87.5 59.2 136 174 Dose (mg/kg) 0.274 0.288 0.283 0.2780.277 Vol. dosed 1.37 1.44 1.42 1.39 1.39 (mL) C_(max) (ng/mL) 188 87.559.2 136 174 t_(max) (hr) 0.75 1.0 1.0 1.0 1.0 t_(1/2) ND² ND³ ND³ ND³ND³ MRT_(last) (hr) 0.677 0.695 0.678 0.716 0.655 AUC_(last) 114 45.731.4 65.4 98.9 (hr · ng/mL) AUC_(∞) ND² ND³ ND³ ND³ ND³ (hr · ng/mL)AUC_(last)/D 4.55 1.53 1.25 2.62 3.95 (hr · kg · ng/ mL/mg) AUC_(∞)/DND² ND³ ND³ ND³ ND³ (hr · kg · ng/ mL/mg) 1. Dose-normalized by dividingthe parameter by the nominal dose in mg/kg. 2. Not determined due to alack of quantifiable data points trailing the Cmax. 3. Not determinedbecause the terminal elimination phase was not observed. BLOQ = belowthe limit of quantitation (1 ng/mL)

TABLE XV provides the mean and standard deviation for the results ofAnimals 41-50.

TABLE XV Sample time (hr) mean SD 0.033 1.69 1.02 0.067 6.08 4.45 0.112.8 10.2 0.13 18.2 10.7 2.0 27.8 16.7 0.25 38.6 18.6 0.5 77.4 28.7 0.75101 43.7 1.0 112 43.8 Dose (mg/kg) 0.282 0.008 Vol. dosed (mL) 1.42 0.04C_(max) (ng/mL) 116 43.3 t_(max) (hr) 0.90 0.13 t_(1/2) ND ND MRT_(last)(hr) 0.661 0.0312 AUC_(last) (hr · ng/mL) 67.6 269.0 AUC_(∞) (hr ·ng/mL) ND ND AUC_(last)/D 2.70 1.04 (hr · kg · ng/mL/mg) AUC_(∞)/D ND ND(hr · kg · ng/mL/mg)

A Summary of the Average Plasma Exposures for CBD After OralAdministration of the Compositions Disclosed in Tables 1 to 8 at 25mg/kg of CBD in Male Sprague-Dawley Rats

TABLE XVI Dose-normalized Test Cmax t_(max) AUC_(last) AUC_(last) GroupComposition (ng/mL) (hr) (hr · ng/mL) (hr · kg · ng/mL/mg) 1 Table 1 1120.83 64.6 2.58 2 Table 2 235 0.75 135 5.39 3 Table 3 25.8 0.95 13.20.527 4 Table 4 77.9 0.90 15.7 1.83 5 Table 5 113 0.90 67.6 2.70

A Summary of the Average Plasma Exposures for CBD After OralAdministration of the Composition Disclosed in Tables 1 to 5 at 25 mg/kgof CBD in Male Sprague-Dawley Rats

TABLE XVII Dose-normalized Test Cmax t_(max) AUC_(last) AUC_(last) GroupComposition (ng/mL) (hr) (hr · ng/mL) (hr · kg · ng/mL/mg) 1 Table 1 1120.83 64.6 2.58 2 Table 2 235 0.75 135 5.39 3 Table 3 25.8 0.95 13.20.527 4 Table 4 77.9 0.90 15.7 1.83 5 Table 5 113 0.90 67.6 2.70

Concentrations of CBD in Brain Tissue After Oral Administration of aComposition from Table 1 at 25 mg/kg of CBD in Male Sprague-Dawley Rats(Group 1)

TABLE XVII Brain Brain homog- homog- Brain Brain enate enate tissue TimeAnim mass volume conc. conc. Mean SD (hr) No. (g) (mL) (ng/mL) (ng/g)(ng/g) (ng/g) 8.0 1 1.85 5.55 14.1 42.3 46.8 12.3 2 1.92 5.76 17.2 51.63 1.86 5.58 22.0 66.0 4 1.89 5.67 12.0 36.0 5 1.66 4.98 12.7 38.1 24 61.94 5.82 0.946 2.84 2.49 0.804 7 1.87 5.61 0.625 1.88 8 1.88 5.64 0.7812.34 9 1.82 5.46 0.566 1.70 10 1.82 5.46 1.23 3.69

Concentrations of CBD in Brain Tissue After Oral Administration of theComposition of Table 2 at 25 mg/kg of CBD in Male Sprague-Dawley Rats(Group 2)

TABLE XIX Brain Brain homog- homog- Brain Brain enate enate tissue TimeAnim mass volume conc. conc. Mean SD (hr) No. (g) (mL) (ng/mL) (ng/g)(ng/g) (ng/g) 8.0 21 1.88 5.64 48.8 146 275 155 22 1.82 5.46 130 390 231.77 5.31 38.1 114 24 1.88 5.64 93.6 251 25 1.78 5.34 158 474 24 26 1.925.76 2.78 8.34 6.21 2.00 27 1.69 5.07 2.21 6.63 28 1.92 5.76 2.48 7.4429 1.86 5.58 1.82 5.46 30 1.84 5.52 1.06 3.18

Concentrations of CBD in Brain Tissue After Oral Administration of theComposition of Table 3 at 25 mg/kg of CBD in Male Sprague-Dawley Rats(Group 3)

TABLE XX Brain Brain homog- homog- Brain Brain enate enate tissue TimeAnim mass volume conc. conc. Mean SD (hr) No. (g) (mL) (ng/mL) (ng/g)(ng/g) (ng/g) 8.0 41 1.94 5.82 3.36 10.1 13.5 9.11 42 1.92 5.76 3.3210.0 43 2.04 6.12 1.77 5.31 44 1.86 5.58 4.46 13.4 45 2.12 6.36 9.6729.0 24 46 1.74 5.22 BLOQ ND ND ND 47 1.94 5.82 BLOQ ND 48 1.92 5.76BLOQ ND 49 1.84 5.52 BLOQ ND 50 1.99 5.97 BLOQ ND

Concentrations of CBD in Brain Tissue After Oral Administration theComposition from Table 4 at 25 mg/kg of CBD in Male Sprague-Dawley Rats(Group 5)

TABLE XXI Brain Brain homog- homog- Brain Brain enate enate tissue TimeAnim mass volume conc. conc. Mean SD (hr) No. (g) (mL) (ng/mL) (ng/g)(ng/g) (ng/g) 8.0 61 1.87 5.61 31.9 95.7 167 115 62 1.95 5.85 77.7 23363 1.90 5.70 113 339 64 1.88 5.64 22.6 67.8 65 1.84 5.52 33.7 101 24 661.78 5.34 1.17 3.51 2.78 1.00 67 1.87 5.61 1.76 5.28 68 1.73 5.19 1.213.63 69 1.81 5.43 1.33 3.99 70 1.74 5.22 0.834 2.50

Concentrations of CBD in Brain Tissue After Oral Administration of theComposition of Table 5 at 25 mg/kg of CBD in Male Sprague-Dawley Rats(Group 5)

TABLE XXII Brain Brain homog- homog- Brain Brain enate enate tissue TimeAnim mass volume conc. conc. Mean SD (hr) No. (g) (mL) (ng/mL) (ng/g)(ng/g) (ng/g) 8.0 71 1.79 5.37 38.9 117 142 38.3 72 4.91 5.73 42.9 12973 1.94 5.82 70.1 210 74 1.74 5.22 42.2 127 75 1.79 5.37 43.2 130 24 761.86 5.58 1.94 5.82 5.33 0.703 77 2.04 6.12 1.62 4.86 78 1.94 5.82 1.785.34 79 1.94 5.82 1.48 4.44 80 1.92 5.76 2.06 6.18Human Studies

The following compositions were used in controlled human clinical trialsmeasuring the difference in systolic blood pressure (SBP), mean arterialpressure (MSP) and diastolic blood pressure (DBP) between volunteerstaking a composition disclosed in Table 6 or Table 7 versus placebo overa 24 hour period.

TABLE 6 Ingredients Mass (mg) Percent % Cannabidiol oil¹ 30.83 4.21 Higholeic acid sunflower oil 61.67 8.41 Tapioca starch 492.50 67.1 Ox bileextract² 65.00 8.87 Silicon dioxide 18.00 2.69 Tapioca flour 65.00 8.87Total 733.00 100 1. contains 85.34 % cannabidiol for an effective amountof 25 mg. 2. contains 45-55% deoxy cholic acid, taurocholate andglycocholic acid

TABLE 7 Ingredients Mass (mg) Percent % Cannabidiol oil¹ 87.1 12.44 Higholeic acid sunflower oil 174.20 24.89 Tapioca starch 164.84 23.55Aeroperl ® 300 158.86 22.69 Ox bile extract² 65.00 9.29 Microcrystallinecellulose 50.00 7.14 Total 700.00 100 1. contains 90.64 % cannabidiolfor an effective amount of 75 mg. 2. contains 45-55% deoxy cholic acid,taurocholate and glycocholic acid

The composition disclosed in Table 8 is used for a human clinical trial.

TABLE 8 Ingredients Mass (mg) Percent % Cannabidiol¹ 75.76 13.29 Higholeic acid olive oil 151.52 26.58 Partek-M mannitol 142.95 25.08Aeroperl ® 300 142.95 25.08 Deoxy cholic acid 6.8 1.2 Microcrystallinecellulose 50.00 8.77 Total 570.00 100 1. contains 99% cannabidiol for aneffective amount of 75 mg.

The composition disclosed in Table 6 was administered to humanvolunteers with mild to moderate hypertension under the followingprotocol. During a 24-hour study, 16 volunteers in each group wereadministered the composition of Table 6 or a placebo at selected times,t=0, t=13 hours, and t=22 hours. The results are depicted in FIG. 11 .The results of subjects given the composition containing the compositionin Table 6 are reflected in the dashed line with solid circles (●) andthe subjects given the placebo are reflected in the solid line and opencircles (○). As depicted in FIG. 11 the approximately 7% difference insystolic blood pressure (SBP) continued after the ambulatory period,i.e., during the sleep period.

FIG. 12 reflects the mean arterial pressures (MAP) of the two groups.During the ambulatory period, volunteers averaged a significantreduction of 5.3% in MAP versus the group given a placebo. FIG. 13reflects the reduction of 3.5% in diastolic pressure versus placebo.

An analysis of the physical activity levels of the volunteers with mildto moderate hypertension during the 24-hour monitored period showed nosignificant differences in activity between the placebo and thecomposition from Table 6 treated volunteers, indicating that theobserved differences in BP were not due to disparate physical movementor demands.

Arterial stiffness is a strong predictor of disease in humans. Theimpacts of increased arterial stiffness are not limited only to coronaryheart disease such as hypertension, but also include other diseasestates such as diabetes mellitus, renal disease and more. It can also bea prognostic marker for cardiovascular events and all-cause mortality,even in asymptomatic individuals without overt cardiovascular disease.

The efficacy of blood pressure treatment and differences in efficacybetween different types of antihypertensive agents is stronglycorrelated with measuring arterial stiffness, whereby the significantblood pressure reduction effects depicted in FIGS. 11 to 13 appear tohave been at least partially due to these improvements in arterialstiffness. Arterial stiffness results from this study are summarized inTable XXIII below. All comparisons between the subject given thecomposition and placebo statistically significant (p<0.01).

TABLE XXII Composition Measurement Table 6 Placebo Pulse Wave Velocity8.1 ± 0.3 m/s 8..31 ± 0.3 m/s Augmentation Index 28.4 ± 1.4% 32.3 ± 1.3%Augmentation Index corrected 27.8 ± 1.3% 30.4 ± 1.3% to heart rate of 75BPM Augmentation pressure 12.0 ± 1.0 mmHg 14.6 ± 1.0 mmHg

In this study 60 volunteers between the ages of 45-70 administeringthree 150 mg doses of the composition disclosed in Table 7, every dayfor 6-weeks. This study is a double blinded, randomized cross-overdesign, and utilizes a placebo control. Some volunteers are alreadyusing leading standard of care hypertension drugs such as ACE inhibitorswith or without diuretics to assist in the evaluation of the compositiondisclosed in Table 7 to determine the efficacy of this composition withand without other hypertension treatments. The purpose of this study isto evaluate the potential for longer term health benefits.

This study is more comprehensive than the study conducted above and manytypes of analysis are performed including 24-hour ambulatory bloodpressure (which is the primary outcome); arterial stiffness andautonomic balance; brain structure and function through brain magneticresonance imaging (“MRI”); blood biomarkers (including lipids such ascholesterol and more); renal, hepatic, sleep quality/daytimesleepiness/sleep disorders; actigraphy, geriatric depression scale,perceived stress, and Beck anxiety inventory.

Other advantages which are obvious, and which are inherent to thedisclosure will be evident to one skilled in the art. It will beunderstood that certain features and sub-combinations are of utility andmay be employed without reference to other features andsub-combinations. This is contemplated by and is within the scope of theclaims. Since many possible embodiments can be made relating to thisdisclosure without departing from the scope thereof, it is to beunderstood that all matter herein set forth or shown in the accompanyingdrawings is to be interpreted as illustrative and not in a limitingsense.

What is claimed is:
 1. A composition for treating hypertension in ahuman, consisting of: a) from about 0.5% to about 20% by weight of CBDoil wherein the CBD oil contains from about 80% to about 92% by weightof cannabidiol; b) from about 0.5% to about 60% by weight of sunfloweroil; c) from about 5% to about 20% by weight of a bile salt wherein thebile salt is selected from the group consisting of deoxycholic acid,taurocholate acid, glycocholic acid, or mixtures thereof; and (d) thebalance being from about 20% to about 99% by weight of one or morecarriers is selected from the group consisting of colloidal silicondioxide, tapioca starch, or mixtures thereof.
 2. The compositionaccording to claim 1, consisting of from about 2% to about 5% by weightof CBD oil.
 3. The composition according to claim 1, consisting of fromabout 6% to about 15% by weight of sunflower oil.
 4. A composition fortreating hypertension, consisting of: a) from about 5 mg to about 15 mgby weight of CBD oil wherein the CBD oil contains from about 80% toabout 92% by weight of cannabidiol; b) from about 5 mg to about 45 mg byweight of sunflower oil; c) from about 1 mg to about 10 mg by weight ofone or more bile salts wherein the bile salt is selected from the groupconsisting of deoxycholic acid, taurocholate, glycocholic acid ormixtures thereof; and d) the balance being one or more carriers selectedfrom the group consisting of colloidal silicon dioxide, tapioca starch,or mixtures thereof.
 5. The composition according to claim 4, whereinthe composition is consisting of from 5 mg to about 12 mg by weight ofCBD oil.
 6. The composition according to claim 4, consisting of fromabout 5 to about 30 mg by weight of sunflower oil.
 7. The compositionaccording to claim 4, wherein the bile salt is deoxycholic acid.
 8. Acomposition for treating hypertension, consisting of: a) from about 10mg to about 100 mg by weight of CBD oil; b) from about 10 mg to about300 mg by weight of sunflower oil; c) from about 60 to about 70 mg byweight of one or more bile salts wherein the bile salt is selected fromthe group consisting of deoxycholic acid, taurocholate, glycocholic acidor mixtures thereof; and d) from about 200 mg to about 800 mg by weightof one or more carriers wherein the carriers are selected from the groupconsisting of tapioca starch, tapioca flour, silicon dioxide, andmixture thereof.
 9. The composition according to claim 8, consisting of:a) from about 25 mg to about 40 mg by weight of CBD oil; b) from about50 mg to about 80 mg by weight of sunflower oil; c) from about 60 mg toabout 70 mg by weight of one or more bile salts wherein the bile salt isselected from the group consisting of deoxycholic acid, taurocholate,glycocholic acid or mixtures thereof; and d) from about 500 mg to about600 mg by weight of one or more carriers wherein the carriers areselected from the group consisting of tapioca starch, tapioca flour,silicon dioxide, and mixture thereof.
 10. The composition according toclaim 8, consisting of: a) from about 75 mg to about 90 mg by weight ofCBD oil; b) from about 55 mg to about 70 mg by weight of sunflower oil;c) from about 60 mg to about 70 mg by weight of one or more bile saltswherein the bile salt is selected from the group consisting ofdeoxycholic acid, taurocholate, glycocholic acid or mixtures thereof;and d) from about 500 mg to about 600 mg by weight of one or morecarriers wherein the carriers are selected from the group consisting oftapioca starch, tapioca flour, silicon dioxide, and mixture thereof. 11.The composition according to claim 8, consisting of: a) from about 80 mgto about 95 mg by weight of CBD oil; b) from about 160 mg to about 190mg by weight of sunflower oil; c) from about 60 mg to about 70 mg byweight of one or more bile salts wherein the bile salt is selected fromthe group consisting of deoxycholic acid, taurocholate, glycocholic acidor mixtures thereof; and d) from about 300 mg to about 400 mg by weightof one or more carriers wherein the carriers are selected from the groupconsisting of mannitol, silicon dioxide, colloidal silicon dioxide,microcrystalline cellulose, and mixture thereof.
 12. The compositionaccording to claim 8, consisting of: a) about 81 mg by weight of CBDoil; b) about 62 mg by weight of sunflower oil; c) about 65 mg by weightof one more bile salts wherein the bile salt is selected from the groupconsisting of deoxycholic acid, taurocholate, glycocholic acid ormixtures thereof; and d) about 575 mg by weight of one or more carrierswherein the carriers are selected from the group consisting of tapiocastarch, tapioca flour, silicon dioxide, and mixture thereof.
 13. Thecomposition according to claim 8, consisting of: a) from about 80 mg toabout 95 mg by weight of CBD oil; b) from about 160 mg to about 190 mgby weight of sunflower oil; c) from about 60 to about 70 mg by weight ofone or more bile salts wherein the bile salt is selected from the groupconsisting of deoxycholic acid, taurocholate, glycocholic acid ormixtures thereof; and d) from about 300 mg to about 400 mg by weight ofone or more carriers wherein the carriers are selected from the groupconsisting of from mannitol, silicon dioxide, colloidal silicon dioxide,microcrystalline cellulose, and mixture thereof.
 14. The compositionaccording to claim 8, consisting of: a) about 87 mg by weight of CBDoil; b) about 174 mg by weight of sunflower oil; c) about 65 mg byweight one or more bile salts wherein the bile salt is selected from thegroup consisting of deoxycholic acid, taurocholate, glycocholic acid ormixtures thereof; and d) about 375 mg by weight of one or more carrierswherein the carriers are selected from the group consisting of mannitol,silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose.15. The composition according to claim 8, consisting of: a) from about70 mg to about 80 mg by weight of CBD oil; b) from about 145 mg to about160 mg by weight of sunflower oil; c) from about 5 mg to about 8 mg byweight of one or more bile salts wherein the bile salt is selected fromthe group consisting of deoxycholic acid, taurocholate, glycocholic acidor mixtures thereof; and d) from about 300 mg to about 350 mg by weightof one or more carriers wherein the carriers are selected from the groupconsisting of mannitol, silicon dioxide, colloidal silicon dioxide,microcrystalline cellulose, and mixture thereof.
 16. The compositionaccording to claim 8, consisting of: a) about 76 mg by weight of CBDoil; b) about 152 mg by weight of sunflower oil; c) about 7 mg by weightof one or more bile salts wherein the bile salt is selected from thegroup consisting of deoxycholic acid, taurocholate, glycocholic acid ormixtures thereof; and d) about 335 mg by weight of one or more carrierswherein the carriers are selected from the group consisting of mannitol,silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose,and mixture thereof.
 17. A method for treating hypertension in a subjectin need of treatment, comprising administering to a subject in need aneffective amount of a composition consisting of: a) from about 0.5% toabout 20% by weight of CBD oil; b) from about 0.5% to about 60% byweight of sunflower oil; c) from about 5% to about 20% by weight of abile salt wherein the bile salt is selected from the group consisting ofdeoxycholic acid, taurocholate acid, glycocholic acid, or mixturesthereof; and (d) the balance being from about 20% to about 99% by weightof one or more carriers selected from the group consisting of colloidalsilicon dioxide, tapioca starch, or mixtures thereof.
 18. The methodaccording to claim 17, further comprising from about 5% to about 15% ofa bile salt.